Mixed Ionic Electronic Conductors:  Devices, Systems and Methods of Use

ABSTRACT

The invention provides a variety of novel devices, systems, and methods of utilizing mixed-ionic-electronic conductor (MIEC) materials adapted to function with an applied current or potential. The materials, as part of a circuit, are placed in contact with a part of a human or nonhuman animal body. A sodium selective membrane system utilizing the MIEC is also described.

RELATED APPLICATIONS

This application is a Continuation-In-Part of U.S. patent applicationSer. No. 16/080,303 filed 27 Aug. 2018, which was a U.S. national stagefiling of PCT/US18/026981 filed 10 Apr. 2018 which claimed the benefitof U.S. Provisional Patent Application Ser. No. 62/483,942 filed 10 Apr.2017. U.S. patent application Ser. No. 16/080,303 is incorporated hereinas if reproduced in full below. This application also claims the benefitof U.S. Provisional Patent Application Ser. No. 62/743,517 filed 9 Oct.2018.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a medical apparatus, comprising:an anode and a cathode; and a MIEC disposed between the anode andcathode. The MIEC comprises a drug or therapeutic agent is dispersed inan elastic MIEC comprising electrical conductor, ionic conductor, andelastomeric particles. The drug or therapeutic agents can be any one, ora combination of, the drugs or therapeutic agents described below. Insome embodiments, the anode and cathode are parallel bars. Preferably,the apparatus does not contain a conductive ring. This apparatus may beused to heal wounds by passing a current through the device toresistively generate heat.

The invention also includes methods of making the MIEC wherein the drugor therapeutic agent is dispersed in an aqueous dispersion along withthe high aspect ratio (at least 10× length to height and width)electrical conductor, ionic conductor, and elastomeric particles.

In another aspect, the invention provides a method of treating a humanor nonhuman animal, comprising: providing an apparatus comprising a MIECdisposed between an anode and cathode; wherein the MIEC comprises anelectrical conductor, ionic conductor, and elastomeric particles;applying the MIEC directly in contact with the skin of the human ornonhuman animal; and passing an electrical current through the MIEC. Insome embodiments, the current heats the MIEC, preferably to atemperature in the range of 35 to 40° C. In some embodiments, the MIECcomprises a dispersed drug or therapeutic agent; and a current is passedthrough the MIEC increasing the permeability of the skin. In someembodiments, the MIEC is placed in direct contact with a wound in theskin. Preferably, the method does not utilize a hydrogel.

In a further aspect, the invention provides a wound healing system,comprising a dressing, wherein the dressing comprises a MIEC. The MIECcomprises a drug or therapeutic agent is dispersed in the elastic MIECcomprising CNTs, ionic conductor, and elastomeric particles. In someembodiments, the wound healing system further comprises one or anycombination of the following: wherein the dressing comprises alginates;wherein the drug or therapeutic agent comprises epidermal growth factor;wherein the MIEC comprises 10-50 wt % CNT, 20-50 wt % ionic conductor,and 5-70 wt % elastomer; wherein the dressing comprises at least 20 mass% CNTs, or at least 50 mass % CNTs, or at least 70 mass % CNTs, or atleast 90 mass % CNTs; or conversely, wherein the dressing comprises atmost 80 mass %, 50%, 30%, or at most 20 mass % elastomer or otherpolymer.

In a related aspect, the invention provides a method of healing a wound,comprising: applying the dressing of in direct contact with a wound. Insome embodiments, the dressing is applied to the wound byelectrospinning. The invention also includes a method of healing awound, comprising: applying the dressing over a wound and passingcurrent through the dressing. Typically, the current resistively heatsthe dressing which assists the healing. The invention also includes amethod of applying a dressing onto a wound, comprising applying an MIECdispersion onto a wound and allowing the MIEC to harden. Alternatively,the MIEC can be applied onto a gauze over a wound. Preferably, the MIECcomprises CNTs, ionic conductor, and elastomeric particles.

In a further aspect, the invention provides a method of forming a deepnerve electrode, comprising: drawing a CNT fiber having a diameter offrom 10 to 500 μm or, alternatively, providing a core fiber and coatingthe core fiber with CNTs to form a CNT fiber having a core coated withCNTs such that the core coated with CNTs has a diameter of from 10 to500 μm; coating the fiber with a first insulating polymer, exceptleaving a tip exposed at the proximal end; applying a CNT/ionicconductor coating over the first polymer while leaving exposed the tipand a portion of the first polymer at the proximal end; and coating thefiber with a second insulating polymer, except leaving the tip and aportion of the first polymer and a portion of the CNT/ionic conductorcoating exposed at the proximal end. In a preferred embodiment, themethod further comprises: applying a second CNT/ionic conductor coatingover the second insulating polymer, except leaving the tip and a portionof the first polymer and a portion of the CNT/ionic conductor coating,and a portion of the second polymer exposed at the proximal end.

In another aspect, the invention provides a deep nerve electrode,comprising: a CNT fiber core having a diameter of from 10 to 500 μm or,alternatively, a core fiber coated with CNTs such that the core coatedwith CNTs has a diameter of from 10 to 500 μm; a first insulatingpolymer coating the CNT fiber core, except leaving a tip of the CNTfiber core exposed at the proximal end; a CNT/ionic conductor coatingover the first polymer that leaves exposed the tip and a portion of thefirst polymer at the proximal end; and a second insulating polymercoating over the CNT/ionic conductor coating, except leaving the tip anda portion of the first polymer and a portion of the CNT/ionic conductorcoating exposed at the proximal end.

The invention also includes a cuff comprising a plurality of the deepnerve electrodes described herein. The invention also includes a methodof recording or stimulating a nerve in a human or a nonhuman animal,comprising: inserting the deep nerve electrode of claim 3 into a nerveinterfascicularly or intrafascicularly. If a core fiber is used, thecore fiber is preferably an insulating polymer.

In yet another aspect, the invention provides a method of obtaining anEEG, ECG, or EMG, comprising utilizing an electrode of the typedescribed herein, without use of a hydrogel, to obtain a measurement foran EEG, ECG, or EMG.

In another aspect, the invention provides a method of forming a dryelectrode, comprising: mixing CNTs and ionic conductor and elastomerparticles in an aqueous dispersion to form a CNT/ionicconductor/elastomer dispersion; providing a substrate comprising anelectrical wire on the surface; depositing a conductive adhesivecomposition over the wire; applying the CNT/ionic conductor/elastomerdispersion over the conductive adhesive composition; and curing toharden the dispersion to make an MIEC connected to an electrical wire.The invention can include a step of curing the conductive adhesivecomposition prior to applying the dispersion. The electrical wire can beattached to the surface with adhesive or a mechanical fastener.

In a further aspect, the invention provides a vaccine system,comprising: an MIEC comprising a vaccine dispersed therein. The MIEC isdisposed between an anode and a cathode. In some embodiments, theinvention provides a microneedle skin patch comprising the vaccinesystem. The body of the microneedle skin patch is preferably made fromMIEC. The invention also includes methods of using the vaccine system;in some preferred embodiments, the MIEC is stored in reservoirs in thebody of a human or nonhuman animal.

In another aspect, the invention provides a method of delivering avaccine using the vaccine system. In preferred embodiments, this methodof storing vaccines can maintain vaccine activity with little or norefrigeration.

In another aspect, the invention provides an epicardial mesh,comprising: a mesh comprising an MIEC configured to be placed around theheart of a human or nonhuman animal; wherein the MIEC comprises anasymmetric electrical conductor, an ionic conductor, and elastomericparticles. The invention also provides a method of treating a human ornonhuman animal, comprising: placing the mesh of claim 1 around theheart of the human or nonhuman animal.

In a further aspect, the invention provides a method of sensing pressurechanges within the body of a human or nonhuman animal, comprising:placing a MIEC material within the body of the human or nonhuman animal;and measuring changes of impedance through the MIEC as the body moves.In some embodiments, the method provides a MIEC precursor compositioncomprises a polyionic material with polymerizable side groups; injectingthe MIEC precursor into a cavity, recess or channel inside the human ornonhuman animal; polymerizing the polyionic material to form an MIECelastic solid body within, and conforming to the shape of, the cavity,recess or channel. Preferably, the MIEC comprises CNTs. The method mayfurther comprise attaching electrical leads to the MIEC body. In someembodiments, the UV light is used to polymerize the polyionic material.

In another embodiment, the invention provides an ion sensing device,comprising: a working electrode and a reference electrode connected toopposite sides of a MIEC membrane wherein the reference electrode isshielded from the environment; and a voltage meter disposed between theworking electrode and reference electrode. Preferably, the MIECcomprises CNTs. In some embodiments, the MIEC comprises HA, zwitterionic brushes, or Nafion. The reference electrode may be shielded fromthe environment by encapsulation in the MIEC. In some embodiments, theMIEC membrane is bonded to a substrate. The ion sensing device can bedisposed in an aqueous environment and the invention includes systemscomprising the aqueous environment. The ion sensing device can bedisposed in a body of a human or nonhuman animal and exposed to blood.The invention also includes a method of measuring ion concentration,comprising placing the ion sensing device of any of the above claims inan aqueous environment and detecting a voltage.

In a further embodiment, the invention provides a sensor for operationin aqueous environment, comprising: an active surface comprising apolymeric ionic conductor coated on the active surface. In someembodiments, the invention includes one or any combination of thefollowing features: wherein the polymeric ionic conductor comprisesNafion; further comprising grafted SBMA; wherein the active surfacecomprises a MIEC; wherein the MIEC comprises a gradient of ionicconductors that increase in concentration with the highest concentrationnear the active surface; wherein the sensor is an electrochemicalsensor; wherein the sensor is a sensor for surface plasmon resonance(SPR). The gradient can be prepared by layer-by-layer fabrication of theelectrode.

In a further aspect, the invention provides a method of monitoring achemical or biological process in an aqueous environment, comprising:disposing a sensor in an aqueous environment, wherein the sensor has anactive surface comprising a polymeric ionic conductor coated on theactive surface; and obtaining a plurality of measurements over time viathe active surface in the aqueous environment. In some embodiments, themeasurements comprise measurements of surface plasmon resonance.

In another aspect, the invention provides a sodium-selective membranesystem, comprising: a composite comprising CNTs, HA, and a polymer;wherein the composite has a thickness of 100 μm or less, preferably 10μm or less, and in some embodiments in the range of 1 to 20 μm; whereinthe composite is disposed in a saline solution that is at least 0.01 Min Na, more preferably at least 0.1 M Na, or in the range of 0.2 to 0.9M Na on at least one side of the membrane. In some embodiments, themembrane system has a length and width that are both at least 10× or atleast 100× greater than thickness. The composite may be a MIEC asdescribed herein. The invention also provides a method of removingsodium from a saline solution, comprising: providing the membrane of anyof claims 1-3 disposed in an apparatus wherein the membrane has a feedside and a permeate side; wherein the saline solution on the feed sideis compressed; and wherein sodium selectively passes through themembrane; e.g., the proportion of Na passing through the membrane is atleast 2×, 5×, or 10× greater than Ca passing through the membrane.

Any of the above aspects may include, in various embodiments, any of thefeatures or any combination of the features provided in the descriptionsherein. The invention includes devices, methods of using devices totreat humans or nonhuman animals. The invention also includes systemsthat comprise devices in combination with the materials and conditionsin which the devices are used.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates an apparatus for iontophoresis.

FIG. 2 is a cross-sectional exploded view of a spinal nerve illustratingthe epineurium around the entire nerve; fascicle, perineurium aroundfascicle, axons, endoneurium around an individual axon, and bloodvessels.

FIG. 3 illustrates a fabrication process of a deep nerve electrode (DNE)with three contacts.

FIG. 4 illustrates two concepts of multi-contact electrode. Left, theone single micro electrode with multiple contacts. Right, severalmicroelectrode forms a larger, multi-contact electrode.

FIG. 5 illustrates a flexible cuff base holding four microelectrodestogether.

FIG. 6 illustrates a flexible cuff base holds two microelectrodesinserted into the nerve. Each microelectrode shown here has fourindividual contacts. Each microelectrode is inserted into a differentnerve fascicle.

FIG. 7 illustrates an assembly in which a wire is attached to thesubstrate with adhesive, leaving enough to form a connection exposed. Ontop of this is then added silver adhesive, labeled “current collector”in the figure. The silver is allowed to cure. Next a MIEC/elastomerdispersion is applied to that Ag adhesive surface and cured. Aftercuring, this surface becomes the contact with the skin.

FIG. 8 is a schematic illustration of MIEC containing vaccine and ondemand delivery under an applied electric field.

FIG. 9 shows an epicardial mesh (the picture is prior art).

FIG. 10 shows the results of an electrode potential determination for avariety of membranes.

FIG. 11 shows the cross-section of a single compartment cell using anMIEC membrane.

FIG. 12 shows the results of electroimpedance spectroscopy of Z″ vs Z′for MIEC control (left), with Nafion/PEI (furthest right on x-axis at 0on y (Z″) axis), and SBMA (center) surface modifications. The cell wasset up with a MIEC film on a slide partially submerged in a 0.1M NaClsolution with a submerged Ag/AgCl reference electrode and platinum meshcounter electrode. Units are in ohms.

FIG. 13 shows the open circuit potential in an electrolyte cell (0.1MNaCl) of MIEC control and surface modified MIEC films showing the changefrom control.

DESCRIPTION OF MIECS

Mixed-ionic-electronic conductors (MIECs) are an interconnected networkof electrical and ionic conductors in an elastomeric matrix thatprovide: (1) high surface area for efficient capacitivecharge-discharge; (2) high ionic conductivity for low interfacial chargetransfer—where the interfacial charge transfer can be viewed as made upof resistive and capacitive response; (3) low ohmic resistance; and (4)excellent flexibility and toughness.

Electrical and ionic conductors are embedded in a matrix in such a waythat the electrical and ionic elements achieve percolation, i.e., acontinuous interconnected network, at lower loading than would beachieved by simple random mixing. This allows superior electricalperformance to be achieved while retaining good mechanical properties.

The morphology may be controlled by using a polymer latex, also calledan emulsion, in which polymer particles are dispersed in an aqueousphase, to template the organization of the electrical and ionicconductors, as shown in FIG. 1. Examples of suitable dispersions includeelastomeric polymers such as nitrile butadiene rubber, natural rubber,silicone, Kraton-type, silicone acrylic, or polyurethane. Other suitablepolymer lattices include polyvinylidene fluoride or polyvinylidenechloride. In such a dispersion, at least 90 mass % of the polymerparticles are preferably in the range of 50 nm to 10 μm in diameter. Thedispersion is cast and the volatiles (e.g., water) allowed to evaporate.During evaporation, the polymer particles coalesce to form a continuousfill. This process is the common one for creating nitrile gloves.

The electrical and ionic conductors are added to the latex so that theyare dispersed in the aqueous phase. Methods known in the art forbalancing the pH and selecting any necessary dispersing agents can beused. Suitable electrical conductors are those that have high aspectratio and are readily dispersed into aqueous solutions and includecarbon nanotubes, graphene and graphite structures, and metal nanowires.Suitable ionic conductors include sodium hyaluronate, also calledhyaluronic acid, fluorosulfonic acids like Nafion™, sulfatedpolysaccharides and other mucoadhesive type compounds, or otherphosphonic polyvinylsulfonic acids. Likewise, anisotropic ionicconductive particles like graphene oxide and modified graphene oxide maybe used. In some embodiments, HA is preferred due to its tendency tohydrate with the skin, improving the skin contact.

By adding electrical and ionic conductors to the dispersed phase of thelatex, the conductors tend to coat the surface of the polymer particles,but not penetrate. As the latex is dried, the conductors tend to beconfined at the interfaces, creating an interconnecting network, wherethe major phase is elastomeric and a connected thin, layer phase is theelectronic/ionic conductors.

The morphology of this network can be modified by changing the particlesize of the polymer in the latex. Larger particle sizes require lessconductor to reach an interconnected phase. The film formationtemperature is also a tunable parameter that can used to modify thekinetics to achieve various kinetically trapped states. Other methods toachieve better than random mixing include self-assembling orself-stratifying coatings.

In preferred embodiments, carbon nanotubes are the electrical conductorsand hyaluronic acid (HA), or other glycosaminoglycan, along withmoisture and ions, is the ionic conductor. Preferably, the MIECs havehigh conductivity of at least 1000 mS/cm, preferably at least 2000mS/cm, or in the range of 2000 mS/cm to about 4000 mS/cm is desirable.In some preferred embodiments, the MIECs have high moisture retentionsuch that the composite may absorb at least 20% water, up to 50% by masswater (corresponding to 100% of the weight of the dry composite), insome embodiments 20% to 50%, or 35% to 50% water.

In some embodiments, the MIEC can be further characterized by any one orany combination of the following: the electrode comprising 0.1 to 2 wt %CNTs, preferably 0.2 to 1 wt %, in some embodiments 0.5 to 0.8 wt %CNTs; the electrode comprising 0.1 to 5 wt % glycosaminoglycan,preferably 0.4 to 4 wt %, in some embodiments 0.7 to 3 wt %glycosaminoglycan; the electrode comprising 10 to 60 wt % water,preferably 20 to 50 wt %, in some embodiments 30 to 50 wt % water; theelectrode comprising a mass ratio of glycosaminoglycan to CNT in therange of 0.5 to 5, preferably 1 to 3, and in some embodiments 1.5 to2.5; the electrode comprising at least 0.01 wt % Na, or 0.01 to 2 wt %Na, in some embodiments 0.1 to 1 wt % Na; wherein the electrode has athickness and two major surfaces; and wherein at least 30 wt % of theCNTs are disposed on a major surface or within the 10% of the thicknessnear a major surface; wherein the electrode possesses a conductivity of1000 mS/cm to about 3000 mS/cm that changes by less than 10% after 5strain cycles of extending the material by 50% and allowing the materialto contract; wherein the electrode possesses a ratio of partialconductivity of a charge carrier to the total conductivity, transferencenumber, t_(i) of at least 0.10, preferably at least 0.13, in someembodiments in the range of 0.10 to about 0.20 or 0.15 to about 0.20.

In some embodiments the electrode comprises one or more of thefollowing: wherein the electrode has a top and bottom surface, thebottom surface is adapted to contact the skin of a patient, and theelectrode has a graded structure with an increasing ratio of ionicconductor to electrical conductor from the top to the bottom of theelectrode; wherein the gradient is prepared by layer-by-layerfabrication of the electrode, with increasing levels of ionic conductorin successive layers; preferably having at least 3 layers or at least 5layers; wherein the elastomeric particles comprise nitrile butadienerubber, natural rubber, silicone, Kraton-type, silicone acrylic,polyvinylidene fluoride, polyvinylidene chloride, or polyurethane, orcombinations thereof; wherein, in the emulsion prior to curing, at least90 mass % of the polymer particles are in the size range of 50 nm to 10μm in diameter; wherein the electrical conductors have a number averageaspect ratio of height to the smallest width dimension of at least 10;wherein the electrical conductor comprises carbon nanotubes, graphene,graphite structures, and metal nanowires, and combinations thereof;wherein the ionic conductor comprises hyaluronic acid, fluorosulfonicacids like Nafion™, sulfated polysaccharides and other mucoadhesive typecompounds, or other phosphonic polyvinylsulfonic acids, and combinationsthereof; wherein the polymeric or elastomeric polymer comprises anadhesive polymer or wherein the electrode further comprises an adhesivepolymer; and wherein the coalesced polymeric particles comprise afluoropolymer.

The term “carbon nanotube” or “CNT” includes single, double andmultiwall carbon nanotubes and, unless further specified, also includesbundles and other morphologies. The invention is not limited to specifictypes of CNTs. The CNTs can be any combination of these materials, forexample, a CNT composition may include a mixture of single and multiwallCNTs, or it may consist essentially of DWNT and/or MWNT, or it mayconsist essentially of SWNT, etc. CNTs have an aspect ratio (length todiameter) of at least 50, preferably at least 100, and typically morethan 1000. In some embodiments, a CNT network layer is continuous over asubstrate; in some other embodiments, it is formed of rows of CNTnetworks separated by rows of polymer (such as CNTs deposited in agrooved polymer substrate). The CNTs may be made by methods known in theart such as arc discharge, CVD, laser ablation, or HiPco.

Glycosaminoglycans are long unbranched polysaccharides consisting of arepeating disaccharide unit. The repeating unit (except for keratan)consists of an amino sugar (N-acetylglucosamine orN-acetylgalactosamine) along with a uronic sugar (glucuronic acid oriduronic acid) or galactose. Glycosaminoglycans are highly polar.Anionic glycosaminoglycans are characterized by having at some hydroxylprotons replaced by a counter ion; typically an alkali or alkaline earthelement. Examples of glycosaminoglycans include: β-D-glucuronic acid,2-O-sulfo-β-D-glucuronic acid, α-L-iduronic acid, 2-O-sulfo-α-L-iduronicacid, β-D-galactose, 6-O-sulfo-β-D-galactose, β-D-N-acetylgalactosamine,β-D-N-acetylgalactosamine-4-O-sulfate,β-D-N-acetylgalactosamine-6-O-sulfate, β-D-N-acetylgalactosamine-4-O,6-O-sulfate, α-D-N-acetylglucosamine, α-D-N-sulfoglucosamine, andα-D-N-sulfoglucosamine-6-O-sulfate. Hyaluronan is a particularlypreferred glycosaminoglycan and representative of its class.

Sodium hyaluronate is the sodium salt of hyaluronic acid (HA). Hyaluronis a viscoelastic, anionic, nonsulfated glycosaminoglycan polymer (shownbelow). It is found naturally in connective, epithelial, and neuraltissues. Its chemical structure and high molecular weight make it a gooddispersing agent and film former. CNT/HA aqueous dispersion and phasediagram has been reported in the literature (Moulton et al. J. Am. Chem.Soc. 2007, 129(30), 9452). These dispersions may be used to createconductive films by casting the solution onto a substrate and allowingit to dry. However, the resulting films exhibit blistering, i.e. loss ofadhesion, upon exposure to moisture or high humidity. In addition, theysuffer from resistance fluctuations that occur as a result of moisturefluctuations, as HA can expand and contract, changing the junctionresistance between CNT-CNT contacts.

Materials such as sodium hyaluronate are natural products. These may beisolated from animal sources or extracted from bacteria.

The invention is often characterized by the term “comprising” whichmeans “including,” and does not exclude additional components. Forexample, the phrase “a dispersion comprising CNTs and an anionicglycosaminoglycan” does not exclude additional components and thedispersion may contain, for example, multiple types ofglycosaminoglycan. In narrower aspects, the term “comprising” may bereplaced by the more restrictive terms “consisting essentially of” or“consisting of.”

In some embodiments, the ionic element is organized into a gradientstructure, getting progressively richer as the material gets closer tothe skin. The electrode performance is improved by introducing a smoothtransition from electronic conduction interface (from the currentcollector/Electrode interface) to ionic conduction interface (from theskin-to-electrode-interface). A gradient can be prepared bylayer-by-layer fabrication of the electrode, with increasing levels ofionic conductor in successive layers.

Transdermal Drug Delivery, Wound Healing

Iontophoresis is a means by which charged substances are transportedacross the skin by using a voltage gradient, which allowselectrophoresis and/or electro-osmosis. Generally, the devices employtwo electrodes that are placed in contact with the skin and connect to apower supply/current control device. One electrode is thedrug-delivering electrode and the other is a counter electrode on adifferent skin site. In an anodal iontophoretic device the drug-deliveryelectrode is an anode/donor reservoir with a positively charged drug insolution, and the counter electrode is a cathode reservoir. With anelectric current, cations move away from the anode and into the skin,and negatively charged ions move from the body into donor reservoir. Thereverse is also possible, with anions moving from the dressing into thebody. DC current, preferably between approximately 1-4 mA, is needed fordelivery. There is a limit to the current density the patient cantolerate. Thus, electrochemical coupling to the skin can be important.

The applied potential causes the charged species, such as drugs, tomigrate from bulk (reservoir) to skin-electrode interfacial (woundedarea) prompting drug to diffuse at a rate into human body according togradient value tailored by electrical potential value. In the absence ofany electrical field, there is not a strong driving force to promotespecie diffusion from reservoir to wounded area (though could still beuseful as a wound dressing). Also, in the presence of an electricalfield, pores in the skin are opened by a process called electroporation,which promotes skin permeability, which further enhances diffusions.

Generally, in the absence of an electric field, diffusion alone isinsufficient to transport the drug or therapeutic agent from the MIEC.

Traditional electrodes are often Ag/AgCl and use a hydrogel to helpcouple to the skin. The hydrogel increases the electrochemical surfacearea of the Ag/AgCl electrode, which itself has a low geometric surfacearea. However, these systems have limitations for long-term stability,coupling with some drugs, and total efficacy. Solid electrolytes areknown in the prior art (e.g. U.S. Pat. No. 5,376,107). Solidelectrolytes can solve problems of gel and/or liquid based systems;however, transport is more limited and the coupling is not as good.

We have addressed the problem of maintaining a high electrochemicalsurface area and good contact with the skin by using mixed ionicelectronic conductors comprised of a solid electrolyte mixed on amolecular level with electric conductors. By selecting the appropriateelectrolyte, the system can also retain moisture which enhancespermeability of the skin. The MIEC is prepared by co-dispersing ananisotropic conductive filler, such as carbon nanotubes (CNTs),graphene, or silver nanowires with an ionic conducting polymer such assodium hyaluronate, in an aqueous dispersion. To this blend can be addedone or more drugs or therapeutic agents. Therapeutic agents may includeany of those that are commonly delivered by iontophoresis, whichinclude, but are not limited to hydrocortisone, lidocaine, salicylates,dexamethasone, sumatriptan, negatively charged proteins, or any agentthat may be beneficial to pass through the skin. The MIEC may furthercontain optional resins and/or adhesives to improve the film-formationproperties. The resin also encapsulates the drug into a solid form.Appropriate resins include typical pressure sensitive adhesive polymerssuch as acrylics, polyolefins, silicones, or polyurethanes. Preferably,the drug or therapeutic agent comprises an ionic moiety. Examples ofdrugs or therapeutic agents (note that therapeutic agents is a broadterm and includes drugs as well as any compounds that are used toimprove health, plant extracts) comprise those identified as suitablefor iontophoresis such as identified by US Published Patent ApplicationsNos. 20180271983 and 20180271777. These have been described in part as:anesthetics, fat removal compounds, nutrients, nonsteroidalanti-inflammatory drugs (NSAIDs) agents for the treatment of migraine,hair growth modulators, antifungal agents, anti-viral agents, vaccinecomponents, tissue volume enhancing compounds, anti-cellulitetherapeutics, wound healing compounds, compounds useful to effectsmoking cessation, agents for prevention of collagen shrinkage, wrinklerelief compounds such as Botox, skin-lightening compounds, compounds forrelief of bruising, cannabinoids including cannabidiols for thetreatment of epilepsy, compounds for adipolysis, compounds for thetreatment of hyperhidrosis, acne therapeutics, pigments for skincoloration for medical or cosmetic tattooing, sunscreen compounds,hormones, insulin, corn/callous removers, wart removers, and generallyany therapeutic or prophylactic agent for which transdermal delivery isdesired or combinations thereof. As noted above, the delivery may simplyeffect transport across the skin or nails or hair follicles into alocalized subdermal location, such as treatment of nail fungus ormodulation of hair growth, or may effect systemic delivery such as isdesirable in some instances where vaccines are used. For administrationof anesthetics, typical active ingredients include a local anestheticagent or combination of local anesthetic agents. The local anestheticagent may be one or more of the following: benzocaine, lidocaine,tetracaine, bupivacaine, cocaine, etidocaine, mepivacaine, pramoxine,prilocaine, procaine, chloroprocaine, oxyprocaine, proparacaine,ropivacaine, dyclonine, dibucaine, propoxycaine, chloroxylenol,cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine,propoxycaine, pyrrocaine, risocaine, rodocaine, and pharmaceuticallyacceptable derivatives and bioisosteres thereof. Combinations ofanesthetic agents may also be used.

The acylation of protein thus provides a negative charge to the proteinby virtue of liberating the carboxyl group not bound to the protein.Typical suitable anhydrides include maleic anhydride, succinicanhydride, glutaric anhydride, citraconic anhydride, methylsuccinicanhydride, itaconic anhydride, methylglutaric anhydride, phthalicanhydride and the like. Any dicarboxylic anhydride is suitable;preferred are succinic anhydride and glutaric anhydride. The use ofdicarboxylic acyl chlorides is theoretically possible, but these tend tobe relatively abrasive, and the use of anhydrides is preferred.

Additional representative active agents include, by way of example andnot for purposes of limitation, bepridil, diltiazen, felodipine,Isradipine, nicardipine, nifedipine, nimodipine, nitredipine, verapamil,dobutamine, isoproterenol, carterolol, labetalol, levobunolol nadolol,penbutolol, pindolol, propranolol, solatol, timolol, acebutolol,atenolol, betaxolol, esmolol, metoprolol, albuterol, bitolterol,isoetharine, metaproterenol, pirbuterol, ritodrine, terbutaline,alclometasone, aldosterone, amcinonide, beclomethasone dipropionate,betamethasone, clobetasol, clocortolone, cortisol, cortisone,corticosterone, desonide, desoximetasone, 11-desoxycorticosterone,11-desoxycortisol, dexamethasone, diflorasone, fludrocortisone,flunisolide, fluocinolone, fluocinonide, fluorometholone,flurandrenolide, halcinonide, hydrocortisone, medrysone,6a-methylprednisolone, mometasone, paramethasone, prednisolone,prednisone, tetrahydrocortisol, triamcinolone, benoxinate, benzocaine,bupivacaine, chloroprocaine, cocaine, dibucaine, dyclonine, etidocaine,isobutamben, lidocaine, mepivacaine, pramoxine, prilocaine, procaine,proparacaine, tetracaine, zolamine hydrochloride, alfentanil, choroform,clonidine, cyclopropane, desflurane, diethyl ether, droperidol,enflurane, etomidate, fentanyl, halothane, isoflurane, ketaminehydrochloride, mepridine, methohexital, methoxyflurane, morphine,propofol, sevoflurane, sufentanil, thiamylal, thiopental, acetominophen,allopurinol, apazone, aspirin, auranofin, aurothioglucose, colchicine,diclofenac, diflunisal, etodolac, fenoprofen, fllurbiprofen, gold sodiumthiomalate, ibuprofen, indomethacin, ketoprofen, meclofenamate,mefenamic acid, meselamine, methyl salicylate, nabumetone, naproxen,oxyphenbutazone, phenacetin, phenylbutazone, piroxican, salicylamide,salicylate, salicylic acid, salsalate, sulfasalazine, sulindac,tolmetin, acetophenazine, chlorpromazine, fluphenazine, mesoridazine,perphenazine, thioridazine, trifluorperazine, triflupromazine,disopyramide, encainide, flecainide, indecanide, mexiletine, moricizine,phenytoin, procainamide, propafenone, quinidine, tocainide, cisapride,domperidone, dronabinol, haloperidol, metoclopramide, nabilone,prochlorperazine, promethazine, thiethylperazine, trimethobenzamide,buprenorphine, butorphanol, codeine, dezocine, diphenoxylate, drocode,hydrocodone, hydromorphone, levallorphan, levorphanol, loperamide,meptazinol, methadone, nalbuphine, nalmefene, nalorphine, naloxone,naltrexone, oxybutynin, oxycodone, oxymorphone, pentazocine,propoxyphene, isosorbide dinditrate, nitroglycerin, theophylline,phenylephrine, ephidrine, pilocarpine, furosemide, tetracycline,chlorpheniramine, ketorolac, ketorolac tromethamine, bromocriptine,guanabenz, prazosin, doxazosin, flufenamic acid, benzonatate,dextromethorphan hydrobromide, noscapine, codeine phosphate,scopolamine, minoxidil, combinations of the above-identified activeagents, and pharmaceutically acceptable salts thereof.

Other representative agents include, but are not limited to,benzodiazepines, such as alprazolan, brotizolam, chlordiazepoxide,clobazam, clonazepam, clorazepate, demoxepam, diazepam, flumazenil,flurazepan, halazepan, lorazepan, midazolam, nitrazepan, nordazepan,oxazepan, prazepam, quazepan, temazepan, triazolan, pharmaceuticallyacceptable salts thereof, and combinations thereof; anticholinergicagents such as anisotropine, atropine, belladonna, clidinium,cyclopentolate, dicyclomine, flavoxate, glycopyrrolate, hexocyclium,homatropine, ipratropium, isopropamide, mepenzolate, methantheline,oxyphencyclimine, pirenzepine, propantheline, telezepine, tridihexethyl,tropicamide, combinations thereof, and pharmaceutically acceptable saltsthereof; estrogens, including but not limited to, 17p-estradiol (orestradiol), 17a-estradiol, chlorotrianisene, methyl estradiol, estriol,equilin, estrone, estropipate, fenestrel, mestranol, quinestrol,estrogen esters (including but not limited to estradiol cypionate,estradiol enanthate, estradiol valerate, estradiol-3-benzoate, estradiolundecylate, and estradiol 16,17-hemisuccinate), ethinyl estradiol,ethinyl estradiol-3-isopropylsulphonate, pharmaceutically acceptablesalts thereof, and combinations thereof; androgens such as danazol,fluoxymesterone, methandrostenolone, methyltestosterone, nandrolone,nandrolone decanoate, nandrolone phenproprionate, oxandrolone,oxymetholone, stanozolol, testolactone, testosterone, testosteronecypionate, testosterone enanthate, testosterone propionate,19-nortestosterone, pharmaceutically acceptable salts thereof, andcombinations thereof; and progestins such as cingestol, ethynodioldiacetate, gestaclone, gestodene, bydroxyprogesterone caproate,levonorgestrel, medroxyprogesterone acetate, megestrol acetate,norgestimate, 17-deacetyl norgestimate, norethindrone, norethindroneacetate, norethynodrel, norgestrel, desogestrel, progesterone,quingestrone, tigestol, pharmaceutically acceptable salts thereof, andcombinations thereof.

The drugs or therapeutic agents can be incorporated into a dressingmatrix. One configuration is shown in FIG. 1. In FIG. 1, an MIECdressing matrix is disposed between an anode and cathode. The MIEC is incontact with a subject's body. The absence of metal ring that is presentin a commercially available device makes this device less likely tobecome damaged during application or storage.

Wound Healing

By incorporating a mixed ionic electronic conductor into wound dressing,the transport reactions related to healing, such as cell, nutrient,oxygen, and water are optimized to occur much faster. Topographicalfactors and the ionic environment play an important role in dictatingtransport and repair of wounds.

The MIEC may be formed as a free-standing film. When the ratio ofpolymer to CNT is in the range of approximately 50 wt. % or less, thedried material will have a network structure, which is often referred toas a CNT network. In preferred embodiments, the MIEC comprises 10-50 wt% CNT, 20-50 wt % ionic conductor, and 5-70 wt % elastomer. The 3Dtopography of this system and the presence of ionic conductors increaseshealing transport reaction. Alternatively, a 3D structure can beprepared by electrospinning the CNT/ionic/polymer dispersion, whichgenerates a non-woven mat of nanofibers. With electrospinning, higherloading of polymer can be provided than 50 wt. % because the topographyis provided by the process. Finally, the dispersion may also be appliedand dried onto to a pre-existing woven or non-woven wound dressing.

The MIEC composition can be applied as a dispersion onto the wound, asthe composition hardens, it forms a form-fitting dressing on the wound.A three-dimensional network is prepared by mixing CNTs and ionicconductors and casting into a film or electrospinning; electrospinningwill give greater range topographic attributes. Other nutrients andmolecules that support cell growth, such as EGF, may be included. Ionicconductors are preferably those that have molecular weight greater than25,000 g/mol to create a stable system—this is selected to preventtransport of ionic conductors into the wound. Sodium hyaluronate and/orsimilar molecules are good because they manage the moisture and arebiocompatible. This patch is placed in contact with the wound; thesystem may also be applied to typical dressings such as non-woven orwoven gauze.

As an alternative embodiment, bus bars can be applied in a parallelarrangement, allowing the application of current across the dressing,which generates heat by resistive heating. Maintaining a desiredtemperature, for example in the range of 35 to 40° C. can support woundhealing.

(3) Decreasing Interfacial Resistance for Implantable Stimulation orRecording Electrodes. The System May be Placed as a Coating; does nothave to be the Whole Material (the Coating May be Only MIEC or PartlyMIEC)

We introduce a new method of fabricating a multi-contact deep nerveelectrode (DNE). This DNE will adapt biocompatible, mixed ionicelectronic conductors based on carbon nanotube (CNTs) composites intothe design. These composites will provide electrodes with flexiblemechanical properties and low interfacial impedance. This design istargeted to ensure the minimum level of invasiveness to the nerve, butgood flexibility to assure chronic mechanic stability of the DNE. ThisDNE can be surgically inserted into individual fascicle due to its smallscale diameter (from 50 to 500 μm for each electrode). The multi-contactdesign for each electrode will provide the user the capability ofmonitoring or stimulating different locations along the nerve withineach fascicle. This design will not only increase the selectivity ofstimulation, but also provide a powerful tool to record the nerve atdifferent levels, allowing researchers to study the functional structureof the nerve. Meanwhile, a multi-electrode cuff holder around the nervewill also be introduced in this disclosure, allowing users tomonitor/stimulate multiple fascicles independently.

There are mainly three types of peripheral nerve electrodes to interfacethe peripheral nerve system: Epineural electrode, Interfascicularelectrode, and Intraneural electrode.¹ The best example of an epineuralelectrode, or cuff electrode, is the Flat Nerve Interfacing Electrode(FINE) from Case Western Reserve University. This type of electrode hasmultiple contacts around the nerve outside the epinerium, providing thecapability of stimulating and recording. Although FINE can provide alimited level of selectivity for stimulating certain fascicles, it stillsuffers from good selectivity for stimulation in cases where a highnumber of fascicles are presenting. For example, in human femoral nerve,the number of fascicles are more than 20. FINE electrode provides noaccess to activate certain fascicles independently.² In addition, FINErequires very low-noise electronics to record neural activity around thenerve, since epineurium is highly resistive.³ As the level ofinvasiveness increases, the selectivity of the electrodes is improved. Aslowly penetrating interfascicular nerve electrode is good an example ofa higher invasiveness interfascicular nerve electrode. It cuts theepineurium with multiple blades in order to put electrodes in betweenthe fascicles.⁴ The invasiveness gets even higher for intraneuralelectrodes, like the Michigan shanks and Utah arrays.⁴ While gettinggood selectivity in recording and stimulating, the high level ofinvasiveness can seriously damage the structure of nerve, making chronicrecording not possible. Other peripheral nerve electrodes with highlevel of invasiveness cannot provide chronic stable recording because ofdamage to the nerve structure and inflammation responses from the nerve.

In this disclosure, we present a way to fabricate the deep nerveelectrode (DNE), which is (1) flexible enough to ensure mechanicallychronic stability (2) and has good selectively for both recording andstimulation.

The basic materials technology is a CNT composite. We have demonstratedtwo highly conductive, mechanically flexible form factors. The first isa thread or filament. High concentration CNT dispersions are lyotropicliquid crystals. When extruded through an orifice into a coagulatingbath, they can be drawn into long filaments, with diameters from 10 to500 um. Due to the high orientation, the filaments have highconductivity, exceeding 25 kS/cm. The second form factor is a coating.Similar dispersions have sufficient viscosity to conformally coatobjects, using known methods such as dip-coating, spray-coating, orprinting. The dried coating is also quite conductive, approx. 3 kS/cm.Both form factors are mechanically durable and flexible; the can beflexed and bent and maintain their properties.

Generally, the limiting factor for an electrode is the efficiency of theelectrochemistry at the interface between the electrode and the body.Likewise, the long-term durability of this interface depends on thesurface of the electrode. We have recently developed mixed ionicelectronic conductors, where the CNTs are embedded in another,biocompatible ionic conductor, such as sodium hyaluronate. These systemslower the interfacial impedance with the electrode. These materials canbe used to create a DNE with multiple contacts (FIG. 3). One example isas follows:

-   -   1. The core CNT wire is prepared by solution spinning a        CNT/ionic conductor dope. The diameter of this filament can be        controlled per the design. This core CNT wire provides the        architecture for the remaining coating. It will also serve as        the first electrode.    -   2. The CNT wire is coated with a biocompatible, insulating        polymer, such as medical-grade silicone polyurethane or        thermoplastic polycarbonate polyurethane used for lead        insulation in pacemakers. The tip is left uncoated.    -   3. A CNT/ionic conductor coating is applied, leaving a region of        insulated section. The electrical connection for the DNE can        also be placed at the bottom during this step.    -   4. The process of sequentially coating with insulator and        conductor is repeated to get the desired number of electrodes.

This CNT based micro electrode can have, for example, a diameter from 10to 500 μm, depending on the applications. The fabricated electrode canhave variable number of contacts, spacing, length and geometry.

Finally, the entire assembly may be coated with a biodegradablelubricant coating to aid with insertion. Alternatively, a final coatingwith the ionic conductor may be sufficient to assist with insertion.

A multi-contact design can allow high level of selectivity for bothstimulating and recording. There are two types of multi-contractelectrode described here. Following the process mentioned in FIG. 3, asingle probe with various contracts can be fabricated, or one couldsimply stack several single-contact microelectrodes together to form amulti-contact compound electrode (FIG. 4, right side).

With a single electrode fabricated in this way, one CNT basedmicroelectrode could be used individually or a group of microelectrodescan be used together. A flexible electrode cuff base can be used to holdmultiple electrodes around a nerve. In the case of severalmicroelectrodes applied at the same time, a flexible cuff base can holdseveral electrodes together (FIG. 5). Each electrode acts independentlywith whatever number of contacts are chosen for each individualelectrode. The flexible base with appropriate size is made ofbiocompatible materials, i.e. biocompatible silicon, with a high levelof flexibility so that it can adapt to the size of the target nerve. Theflexible cuff holds the microelectrodes around the nerve, and eachmicroelectrode can be inserted into the nerve interfascicularly orintrafascicularly (FIG. 6).

There are five major advantages of the microelectrode and its flexiblecuff holder base.

-   -   1. This protocol or design allows the fabrication of        mechanically flexible microelectrodes with a diameter ranging        from 10 to 500 μm. The extremely small size of the electrode        diameter will cause the least amount of damage to the nerve        structure and potential less immune response of the nerve. This        will induce a good chronic recording.    -   2. The design of multi-contact electrode provides the capability        of recording from different levels along the nerve. This enables        switching to a different recording site if one of the contacts        is broken or not recording any more over time. One electrode        enables the recording from inside and outside the nerve        fascicles at the same time, if a microelectrode is inserted into        the nerve with different contacts located inside and outside the        nerve fascicles, or even in different fascicles.    -   3. The cuff holder around the nerve provides a good mechanical        security for each microelectrode. This adds a chronic        mechanically stable feature since the microelectrodes will be        prevented from pulling out of the nerve due to possible fiction        or mechanical force generated by motion between the nerve and        nearby muscle or fatty tissue.    -   4. The cuff holder or base provides the capability of inserting        several microelectrodes around the circumference into the nerve        to record or stimulate different fascicles. This provides the        direct access to certain fascicles and increase the selectivity        by nature.    -   5. Different contacts from different microelectrodes could be        selectively activated to conduct the field steering stimulation,        so that the fascicles in between the electrodes, the ones        without a single microelectrode inserted in, can be electrically        stimulated. This approach will further increase the selectivity        of this system when used as a stimulating tool.        (4) Non-Invasive Recording Including EEG (3-4 kHz) ECG, EMG        (0.5-1 kHz), Bioelectronic Skin Potentials, Etc.

A useful attribute of this technology is its application to variouswearable and comfortable forms, such as foam or fabric. No hydrogel isnecessary to couple to the skin. Mechanical contact can be provided byapplying an elastomeric band around the material or using an elastomeror adhesive as the polymer. This technology addresses motion artifactsin recording electrodes that occurs due to squeeze out of the hydrogel.

(5) Non-Invasive Stimulation

Peripheral nerves can be stimulated to treat neural disease. However,most nerve stimulating interfaces are implanted using an invasivesurgery. To overcome this short coming, non-invasive nerve stimulationcan be implemented using a hydrogel or other ‘wet’ conductive interfaceto transcutaneously stimulate nerves at a reasonable depth below theskin. Unfortunately, this ‘wet’ electrode—skin interface is suboptimalfor long term peripheral nerve stimulation (hours-days). Furthermore,shifts in ‘wet’ electrodes over time interfere with therapeutic efficacyand the location of applied current fields below the skin. We havedeveloped an interface that is capable of long term current steerednon-invasive peripheral nerve stimulation with a mixed ionic dryelectrode to treat neural or non-neural disease.

The mixed ionic electronic conductor has advantages over the prior artin that it forms a stable contact. MIECs provide hybrid functionality ofionic & electronic conduction, high electrochemical adhesion, moistureretention, along with mechanical adhesion to improve contact.

Any peripheral nerve that can be reliably activated through the skin andaffect physiological function is a candidate for the technology proposedhere. For example, peripheral nerve stimulation based therapies to treatdisease (e.g. auricular nerve stimulation for atrial fibrillation ortrigeminal nerve stimulation for migraine). The nerves that can bespecially targeted for non-invasive nerve stimulation are many, and someare listed above for example cases. This technology is proposed to beutilized for nerve stimulation based treatment of disease, andrepresents a new avenue to electrically activate nerve fibers.

In one example, see FIG. 7, the CNTs and ionic conductor (HA) were mixedwith an aqueous nitrile rubber dispersion. A wire is attached to thesubstrate with adhesive, leaving enough to form a connection exposed. Ontop of this is then added silver adhesive, labeled “current collector”in the drawing. The silver is allowed to cure. Next the MIEC/elastomerdispersion is applied to that Ag adhesive surface and cured. Aftercuring, this surface becomes the contact with the skin.

Alternatively, the MIEC/elastomer can be directly connected to the wireby placing the wire on a Teflon release layer, casting theMIEC/elastomer and curing. After curing, the resulting material could bereadily handled. The electrode was held in contact with the skin byplacing a piece of tape over the tops. The following example illustratesa method of making and using an embodiment of the invention:

-   -   Dry Electrode Preparation: Carbon Nanotube (CNTs) and Hyaluronic        Acid (HA) dispersion prepared by ultrasonic dispersion in water.        Mix with nitrile Rubber dispersion (Zeon) by FlacTek® at ˜1700        RPM for 30 seconds.    -   Casting the MIEC A Pt wire was placed on a Teflon mold. The wire        was then taped down on the frame of the Teflon mold and the        wires were pressed onto the mold, so they would lay flat on the        mold. 90 μl of CNTs-HA-Elastomer solution was dispensed straight        on the wire The solution was left to cure over the weekend (˜24        hours at room temperature).    -   Two of these electrodes were attached to the skin of a mouse. A        modulated pulse was applied of approximately 1-1.5 mA and less        than 50 Hz. Showed selective non-invasive modulation of blood        pressure without side effects on heart rate using MIEC        electrodes.        A more adhesive formulation can be prepared by using a different        polymer emulsion. For example, CariFlex™ SIS Emulsion can be        used to form the adhesive.

Any of these systems can be applied to electrodes that would usually usea hydrogel. For example, Ag/AgCl can be coated with the MIEC.

6 the Matrix Provides a Useful Means of Storing and Delivery Vaccines toEliminate Cold Chain.

This concept, in preferred embodiments, addresses issues with cold chainfor vaccines by embedding the vaccine in the MIEC. In the first step thevaccine is encapsulated in an ionic polymer. In the second step theencapsulated polymer is mixed with an electronic conductor to form theMIEC. In the third step the MIEC is added to an elastomer and formedinto a microneedle skin patch. In the fourth step the microneedle skinpatch is formed into desired delivery device. The concept isschematically illustrated in FIG. 8.

The vaccine described in step one includes but not limited tolive-attenuated vaccines, inactivated vaccines, subunit, recombinant,polysaccharide, and conjugate vaccines and toxoid vaccines. The ionicpolymer described in step include cationic, anionic or the mixturethereof. They are exemplified by but not limited to chitosan, poly(N,N′-dimethyl aminoethyl methacrylate), hyaluronic acid, poly(acrylicacid) and the combination thereof. The encapsulation method described inthe first step can be layer by layer coating, particle forming methodssuch as emulsion, suspension or dispersion. The electronic conductordescribed in the second step includes but not limited to single walledCNT, multiwalled CNT, fullerenes, graphene, carbon particles,nanoparticles of Cu, Au, Ag and Pt, conducting polymers such aspolyaniline, polythiophene, poly pyrrole and their mixture thereof. Theelastomers described in the third step includes but not limited tosilicone rubber, natural rubber, synthetic rubber, polyurethaneelastomer and their mixture thereof.

In preferred embodiments, this method of storing vaccines maintainsvaccine activity with no refrigeration.

(7) Epicardial Mesh

The prior art has described epicardial meshes as a way to deliverelectrical impulses to the whole ventricular myocardium, rather thanmerely to small point electrodes in the ventricles. See FIG. 9. This iscarried out by creating conductive and elastomeric materials. Systemshave included CNT-based composites, which had insufficient electricalconductivity and/or poor elasticity due to inadequate dispersion. Othershave looked at silver nanowire (AgNW) networks dispersed in polymerssuch as styrene-butadiene-styrene (SBS) rubber, a biocompatiblethermoplastic polymer. The AgNW/polymer networks have better electricalconductivity; however, these systems do not provide for anelectrochemical response, e.g. the conversion from electronic conductionto ionic conduction; The current in the heart is carried by ions such asNa and K. Thus high bulk DC-conductivity is only one property.

We have applied the use of mixed ionic electronic conductors to controlboth interfacial resistance and capacitive coupling between the materialand the heart. The electronic conductors may be any anisotropicconductor, such as CNT or Ag nanowires. Ag nanowires are preferred whenconductivity greater than 2,000 S/cm is desired. Due the method by whichthese composites are prepared, we can achieve higher conductivity andbetter retention of mechanical properties than bulk mixing. Theelectrical and ionic conductors are mixed with polymer emulsions, whichcan then be cast and/or dried and further processed by melt processing.

(8) Implantable Sensors.

The invention provides a system as an implant or otherwise sensespressure changes. Implantable pressure sensors which are MEMS devices orstiff electronic/semiconductor materials limits the quality of thecontact that can be made with soft tissue in the body, and thus limitstheir sensitivity to pressure changes that are associated with medicallyimportant changes, such as tumor growth or biomechanical processes. Incontrast, MIECs and MIEC polymer matrix composite systems are designedfrom soft, biocompatible materials of any geometry. MIECs can betriggered to form continuous networks, such as a hydrogel, in situ,after injection of pre-cured components, such that the compositeconforms to the shape of a cavity, recess, or channel in vivo. In otherwords, the prepolymer MIEC is injected and fills the shape, and thencrosslinks once in vivo. The ionic/polyionic component can be selectedto possess favorable biocompatibility to allow unperturbed cell growth,or to stimulate growth of cells into the MIEC composite.

Changes in material impedance report for pressure changes within the invivo microenvironment of the implanted sensor. The MIEC is in closecontact with body tissue, when the tissue moves, it puts pressure on theelastic MIEC, causing impedance changes. This change in resistanceoccurs mainly due to changes in the CNT-CNT junctions (resistiveresponse) but also due to changes in the electrochemical double layer.If the MIEC is configured to record changes in impedance, such as byattaching between parallel bus bars or placing a bias to make a fieldeffect transistor, local pressure changes can be monitored. These MIECsensor system applications include, but are not limited to: sensing cellgrowth and particularly for real-time tumor growth monitoring, singlecell biomechanics of filipodia or cytoskeletal actin filament formation,blood pressure monitoring with bioinert components, or for monitoringintracranial pressure after injury or surgical intervention.

The sensor is formed from mixed polyionic electronic materials dopedinto a bioinert polymer matrix that is pre-cured in a desired shape.Dimensions may, in preferred embodiments, be less than 10 μm to avoidforeign body response. In one embodiment, the MIEC body of the sensor isin the shape of a cylinder, preferably having a dimension of 2 μm orless. In another embodiment, the polyionic material is first chemicallyfunctionalized with polymerizable side groups, such vinyl, methacrylic,or norbornyl groups that can later be polymerized in situ to fabricate aconformal tissue sensor. The MIEC body of the sensor can have electricalcontacts on opposite sides of the MIEC implant; in another variation,the MIEC body of the sensor can be inductively coupled from outside thebody.

(11) Sensors—any Kind of Sensor that Will be Electrical Sensing in anAqueous Environment (Water, Blood, Tissue, Salt Water). DifferentSensing Device—Such as but not Limited to Reference or Sensing Electrodefor Hydrogen, or Sodium (or Potassium) Electrode

Typical ion-sensing requires a two-chamber device where a membraneseparates two electrodes at different chemical potential; this resultsin measurable voltage. Our invention creates a similar kind ofphenomenon but on a sub-microscopic level. An ionic conducting material,like Nafion, is dispersed with the electrically conductive material.This eliminates the need for two compartments and greatly simplifies thedesign. A single compartment cell measures changes in ionicconcentration.

The MIEC is on a substrate. The reference electrode is created byattaching wire to the underside of the MIEC, at the interface betweenthe substrate and the MIEC, where it is encapsulated from theenvironment. The working electrode is created by connecting to the topsurface that is exposed to the environment. What is surprising is thatthere is a difference in the chemical potential between these twosurfaces. We hypothesize that this is due to the, largely,two-dimensional structure of CNT networks in MIEC, where conductivity ishigher in-plane than through-plane. The ionic conductor serves as theion-sensing membrane. The MIEC need not be on a substrate, but thereference electrode should be in an encapsulated position.

FIG. 10 shows the results of an electrode potential determination for avariety of membranes. The membrane is placed on a substrate via anadhesive (GhostBond™ in the examples). The sensor, a single compartmentcell, illustrated in cross-section in FIG. 11, is capable of beingattached to the skin.

Translation and commercialization of chemiresistive sensors based oncarbon nanomaterials or SPR sensors have been hampered by poorsensitivity, specificity, and passivation by biofouling. High ionicstrength environments create pinned ions at sensor working surface(Helmholtz double layer), which reduces target sensitivity. Moreover,adsorption/binding of off-target species can cause poor specificity andeventual passivation, which further reduces sensitivity. In thisinvention, active biosensor surfaces (electronic or SPR) are modifiedwith polyionic coatings to reduce false positives and false negatives incomplex biological media. Sensing in biological media poses severalchallenges. Polyionic coatings can improve ion transport and reduceoff-target fouling. Techniques include layer by layer assembly and“grafting-from” by radical polymerization. Polyionic coatings include:incorporation or surface grafting of biopolymer polyelectrolyte such asextracellular matrix or polysaccharide materials, Layer-by-layerassembled in methanol of Nafion/branched polyethyleneimine, “Graftingfrom” SI-ATRP, of sulfo-betaine methacrylate (SBMA) from surface boundbromoisobutyryl bromide. SI-photopolymerization of nanofilms ofSBMA/PEGDA after surface tethering photoinitiators. SI-ROMP ofcarboxynorbornene after surface functionalizing with ROMP initiators.

For electrochemical sensors, the signal can be further enhanced bycreating a mixed ionic electronic conductor, where the aforementionedpolyionic coatings are mixed with electrical conductive elements. Mixingpolyionic materials with electrical conductive elements can increase theelectrical surface area to improve sensitivity. Gradients of increasingproportion of mixed polyionic materials near the outer conductor surfacecan also show improvements in charge transfer from ionic media into orout of the conductor material. The gradient of electronic/mixedpolyionic materials can be further improved by transitioning into theaforementioned coatings or polymeric brushes to extend the gradient ofthe ionic component into the electrolytic aqueous media. Changes incharge transfer and the cell voltage can be seen in FIGS. 12 and 13 forpolyionic surface modifications of Nafion-Polyethyleneimine andSulfobetaine methacrylate (SBMA) surface coatings grafted on to MIECcomposites. The control is the composite without further surfacemodifications.

For implantable sensors, the MIEC can be mixed with a soft, or lowmodulus, polymeric matrix to ensure biocompatibility. Typical currentlyavailable electrode for implantable sensors are composed of high moduluselectronic materials, and have significant translational challenges dueto host rejection and fibrous capsule formation around implant. Lowmodulus elastomers that match or nearly match the modulus of tissue canreduce rejection and graft-vs-host response The low modulus, elastomericpolymeric matrix can include but is not limited to polydimethylsiloxane,polyisoprene, copolymers of styrene-isoprene, or other biocompatible andbioinert matrices. This composite can be fabricated by mixing theelectronic and polyionic components with the polymeric matrix that hasbeen emulsified, or by direct dispersion in a common solvent, thencasting the mixture to be cured or coagulated by heat, photoinitiation,or by solvent evaporation.

Ionic segments of the polymeric ionic conductor can be grafted on apolymer backbone. The ionic segments can be anionic, cationic oramphoteric. One method of grafting ionic segment is via co-polymerizingion-containing monomers with non-ion-containing monomers. Another way ofgrafting ionic segment is via post functionalizing the elastomericpolymer.

Examples of anionic segments include, but not limited to, sulfonic,carboxylic, phosphonic and combinations thereof. Examples of cationicsegments includes alkyl ammonium derivatives such as the N,N-dimethylamino ethyl functionality. Examples of amphoteric segments includes thecombination of anionic and cationic segments.

Examples of grafting anionic segments include, but are not limited to,co-polymerizing anion containing monomer such as styrene sulfonic acidwith non-ion containing monomers such as styrene and butadiene toproduce anion containing styrene-butadiene elastomer, namely sulfonatedstyrene-butadiene elastomer.

Examples of grafting cationic segments include, but are not limited to,co-polymerizing cation containing monomer such as N,N-dimethylaminoethyl methacrylate with non-ion containing monomers such as styreneand butadiene to produce cation containing styrene-butadiene elastomer,namely aminated styrene-butadiene elastomer.

Examples of grafting amphoteric segments include, but are not limitedto, co-polymerizing anion and cation containing monomer such as styrenesulfonic acid and N,N-dimethyl aminoethyl methacrylate with non-ioncontaining monomers such as styrene and butadiene to produce amphotericion containing styrene-butadiene elastomer, namely sulfonated andaminated styrene-butadiene elastomer.

Examples of post functionalizing the elastomeric polymer include, butare not limited to, treating styrene butadiene elastomer with fumingsulfuric acid to produce anion-containing styrene-butadiene elastomer,namely sulfonated styrene-butadiene elastomer.

(12) Membrane Application for Separation of Different Species Such asNa+; K+, Etc.

Sodium or/and Potassium membrane separation has a principal advantageover other separations that it can occur without external energy input.At equilibrium the chemical potentials of permeating Na+ at the feed andpermeate side become the same. For low Na+ concentration, separationmeans that the partial pressures or permeable species become the same atthe feed and permeate side of the membrane.

For an ideal membrane that is ideally permeable for only one species(Na+) the only external energy input needed is the compression work todrive the Na+ to the sequestering location.Mixed-ionic-electronic-conduction membranes are very selective forsodium, high flux, and possible reduced investment costs, thicknesspreferably <100 μm, more preferably <10 μm. The presence of hyaluronicacid in salt form promotes sodium ion mobility resulting on itsdiffusion toward low chemical potential side. Due to high affinity of HAto CNTs, the CNTs prevent HA from leaching out from the membranestructure.

What is claimed:
 1. Medical apparatus, comprising: an anode and acathode; and a MIEC disposed between the anode and cathode; wherein theMIEC comprises a drug or therapeutic agent is dispersed in an elasticMIEC comprising electrical conductor, ionic conductor, and elastomericparticles.
 2. The medical apparatus of claim 1 wherein the drug ortherapeutic agent can be any one, or a combination of the drugs ortherapeutic agents disclosed herein.
 3. The medical apparatus of claim 1wherein the anode and cathode a parallel bars.
 4. The medical apparatusof claim 1 wherein the apparatus does not contain a conductive ring. 5.A method of healing wounds wherein a current is passed through theapparatus of claim
 1. 6. The method of claim 5 wherein the currentpassing through the device to resistively generates heat.
 7. A method oftreating a human or nonhuman animal, comprising: providing an apparatuscomprising a MIEC disposed between an anode and cathode; wherein theMIEC comprises an electrical conductor, ionic conductor, and elastomericparticles; applying the MIEC directly in contact with the skin of thehuman or nonhuman animal; and passing an electrical current through theMIEC.
 8. The method of claim 7 wherein the current heats the MIEC to atemperature in the range of 35 to 40° C.
 9. The method of claim 7wherein the MIEC comprises a dispersed drug or therapeutic agent; andwherein a current passed through the MIEC increases the permeability ofthe skin.
 10. The method of any of claim 7 wherein the method does notutilize a hydrogel.
 11. The method of claim 7 wherein the MIEC is placedin direct contact with a wound in the skin.
 12. A method of making anMIEC material, comprising dispersing a drug or therapeutic agent in anaqueous dispersion along with the high aspect ratio (at least 10× lengthcompared to height and width) electrical conductor, ionic conductor, andelastomeric particles.